The epidernis is the primary interface between the internal milieu of the body and potentially hostile environment. The frequency with which epidermal injury occurs has selected for the evolution of an inducible process which amplifies local host defense (inflammation) while enhancing epidermal repair. This proposal suggests that keratinocytes are central to this process, and that binding of keratinocyte interleukin l (IL-1) to its cell surface receptor (IL-lR) induces an "activated state" in keratinocytes. This activation is reflected by enhanced proliferative capacity and by increased de novo gene expression of inflammatory cytokines, which in turn serve to attract circulating inflammatory cells to sites of injury and activate them in situ. In vitro, binding of IL-1 to the IL-LR fits the straightforward binding equation: [bound IL-IR]= Ka [free IL-1][unbound IL-lR), where Ka is the IL-1/1L-lR association constant. It is predicted that the degree of "activation" (judged by IL-1-induced inflammatory cytokine production) in a population of keratinocytes is proportional to the quantity of (bound IL-lR]. One goal of this proposal is to analyses IL-1 induced cytokine gene expression to test the "it" of this biochemical equation to a biological system. Previously, it was demonstrated that keratinocytes contain but do not secrete IL-1, can regulate "'he": .expression of IL-lR/cell over a range of 1000 fold, and can proliferate and synthesize effector cytokines after the addition of exogenous IL-1. In this proposal, stimuli which influence release of keratinocyte IL-1, regulate expression of keratinocyte IL-LR, and influence keratinocyte IL-LR Ka, will be studied at the level of bioactivity, protein, and mRNA production. In vitro conditions which allow for the independent control of each variable will be sought; these include transfection of keratinocytes with mammalian cDNA expression vectors containing IL-1 and IL-IR cDNA's in sense and antisense orientations. By independently manipulating teach variable in vitro and measuring effector cytokine gene expression, the relationship of [bound IL-1] to keratinocyte state of activation will be assessed. It is proposed that in uninjured skin, the product of Ka, [unbound IL-lR), and (free IL-11 is ;insufficient to generate a (bound IL-LR] required for keratinocyte activation. By this model, increases in any or all of the variables on the right side of the equation will increase [bound IL-1R] sufficiently to activate keratinocytes, thus ultimately inducing inflammation and epidermal hyperproliferation. Psoriasis, a disease characterized by epidermal hyperproliferation and inflammation, will be studied by determining 1) [free IL-1],[unbound IL-1R), and effector cytokine production in tissue section; and 2) whether differences 1) exist in these variables in cultured keratinocytes from psoriatic and normal patients. We propose that inflammatory skin diseases, including psoriasis, reflect disequilibrium in the balance of this highly conserved relationship between IL-1 and the IL-1R in epidermis,